The present invention relates to novel phenyl naphthol compounds which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor xcex2. Further, the present invention relates to methods for using such compounds and to pharmaceutical compositions containing such compounds.
While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence blood levels of serum low density lipoprotein (LDL). Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, replacement therapy, particularly in older individuals, may be restricted by certain detrimental effects from thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor ligands, particularly agonists of the thyroid hormone receptor could lead to specific therapies for these common disorders, while avoiding the cardiovascular and other toxicity of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the xcex2-form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes xcex1 and xcex2. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TRxcex11, TRxcex21 and TRxcex22 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TRxcex21 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TRxcex12 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TRxcex11 isoform is also widely distributed, although its levels are generally lower than those of the TRxcex21 isoform. Whereas many mutations in the TRxcex2 gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TRxcex1 function have not been found.
A growing body of data suggests that many or most effects of thyroid hormones on the heart, and in particular, on the heart rate and rhythm, are mediated through the xcex1-form of the TRxcex11 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues, are mediated more through the xcex2-forms of the receptor. Thus, a TRxcex2-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones, but would elicit many other actions of the hormones. Applicants believe that the xcex1-form of the receptor is primarily associated with heart rate function for the following reasons:
1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRxcex2-forms, and high circulating levels of T4 and T3;
2) there was a tachycardia in the only described patient with a double deletion of the TRxcex2 gene (Takeda et al, J. Clin. Endrocrinol. and Metab. 1992, Vol. 74, p. 49);
3) a double knockout TRxcex1 gene (but not xcex2-gene) in mice resulted in a slower mouse heart rate, as compared to control mice; and
4) western blot analysis of human myocardial TRs show presence of the TRxcex11, TRxcex12 and TRxcex22 proteins, but not TRxcex21.
If these indications are correct, then it may be possible that a TRxcex2-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and, (6) osteoporosis in combination with a bone resorption inhibitor.
In accordance with the illustrative embodiments and demonstrating features of the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I: 
wherein;
R1 is halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-7 cycloalkyl;
R2 and R3 are each independently hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, wherein at least one of R2 and R3 is other than hydrogen;
R4 is a carboxylic acid, or an ester thereof, selected from the group consisting of (CH2)nCOOH, (CH)2COOH, NHCO(CH2)nCOOH, CONH(CH2)nCOOH and NH(CH2)mCOOH;
n is an integer from 0 to 4; and
m is an integer from 1 to 4,
including all prodrug-esters, stereoisomers and pharmaceutically acceptable salts of formula I.
The compounds of formula I are thyroid hormone receptor ligands, and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably the compounds of formula I possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, the compounds of formula I may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene, such as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, skin disorders or diseases and congestive heart failure.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. In particular, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.
Further, in accordance with the present invention, a method is provided for preventing, inhibiting or treating the progression or onset of diseases or disorders associated with the thyroid receptor, particularly, the thyroid receptor-beta, such as the diseases or disorders defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e., human, patient in need of treatment.
The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s) active in the therapeutic areas described herein.
In addition, a method is provided for preventing, inhibiting or treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another type of therapeutic agent, is administered to a mammalian species in need of treatment.
Preferably, compounds of this invention include embodiments of formula I wherein:
R1 is selected from the group consisting of halogen, substituted or unsubstituted C1-3 alkyl and substituted or unsubstituted aryl;
R2 and R3 are each independently hydrogen or chloro, wherein at least one of R2 and R3 is chloro;
R4 is selected from the group consisting of NHCO(CH2)nCOOH, NH(CH2)mCOOH, CONHCH2COOH and CH2COOH;
n is an integer from 0 to 1; and
m is an integer from 1 to 2.
Particularly preferred embodiments include compounds of formula I wherein:
R1 is bromo or substituted or unsubstituted C1-3 alkyl;
R2 and R3 are chloro;
R4 is NHCO(CH2)nCOOH or NH(CH2)mCOOH;
n is an integer from 0 to 1; and
m is an integer from 1 to 2.
Specific examples of the preferred compounds of the invention have the structures: 
or an alkyl ester thereof.
Particularly preferred are compounds of the invention having the structures: 
or alkyl esters thereof, such as the methyl or ethyl ester.